DEAROMATIZATION PROTOCOL FOR THE SYNTHESIS OF meta-SUBSTITUTED PHENOLS

Abstract

The thesis entitled “Dearomatization protocol for the synthesis of meta-substituted phenols” is divided into three chapters, viz. (i) Introduction, (ii) Objectives, Results and Discussion, and (iii) Experimental. We have developed novel, convenient and rapid protocols for the dearomatization of alkoxy phenols for the in situ generation of cyclohexadienones which were further trapped by different dienophiles to synthesis valuable scaffolds viz., bicyclo[2.2.2]octenone derivatives via intermolecular Diels-Alder reaction. To further harness the enone functionality of in situ generated highly reactive cyclohexa-2,4-dienones, we have carried out the Michael addition of some easily accessible nucleophiles to masked o-benzoquinones to furnish diarylsulfones, - arylated 1,3-diones and 5-arylbarbiturates. The Michael addition reaction resulted in the formation of phenols coupled with different templates at its meta-position. Further, we have extended the versatility of our approach for the synthesis of phenol functionalized N- and Oheterocyclic systems that are counted among the high phramoacological profile frameworks especially for neurological disorders. Chapter 1: Introduction Since the 1865, when the concept of aromaticity was introduced to the scientific community, aromatic compounds are widely known for their importance in fundamental and applied chemistry and in result extensive efforts have been made to develop convenient and efficient synthetic strategies for the conversion of planar arenes to high-value added aromatic products. Of particular interest is the dearomatization strategy (disruption of the aromatic system of arenes) as it demonstrates the possibilities for the synthesis of biologically potent sophisticated polycyclic architectures from simple planar aromatic feed stocks. The oxidative dearomatization of phenolic compounds serves as a powerful tool in providing products that are primed for further reaction to synthesize popular structurally complex motifs. So, the advancement of effective and eco-friendly synthetic protocols for the oxidative dearomatization of phenols is highly demanding. It is widely known that the synthesis of meta-substituted phenols possesses a significant challenge of bypassing the normal ortho/para directing effect of iv hydroxyl functionality and hence the synthesis of meta-substituted phenols is formidable. Till date, meta-functionalization has been done either with the involvement of transition metals using harsh conditions or using the directing group strategy that results in lengthy synthetic route and simple-cum-straightforward methods are sporadic in literature. Chapter 2: Objectives, Results and Discussion This chapter deals with the objectives, results and discussion which are divided into six sections. 2.1. Dearomatization protocol and synthesis of bicyclo[2.2.2]octenone derivatives In the first instance, we have thrived a clean and efficient protocol for the oxidative dearomatization of alkoxyphenols with PhIO2 generated in situ from using catalytic amount of iodobenzene in the presence of m-CPBA as terminal oxidant. This in situ generated oxidant PhIO2 readily transforms the 2- and 4-alkoxyphenols into masked ortho-benzoquinones (MOBs) and masked para-benzoquinones (MPBs), respectively. Further, the highly reactive MOBs underwent Diels–Alder reaction with various dienophiles to give bicyclo[2.2.2]octenone scaffolds. This oxidative ketalization Diels-Alder protocol is high yielding and proceeded under mild and eco-friendly conditions. (Scheme 1). Scheme 1: Oxidative dearomatization strategy for the synthesis of bicyclo[2.2.2]octenones. v 2.2. Synthesis of arylsulfonyl catechol derivatives Organo-sulfone chemistry has undergone a renaissance in the past decades as the sulfonyl-derived functional groups such as sulfones, sulfonamides populate a broad range of pharmaceutical active molecules and agrochemicals. Similarly, catechol structural motifs are stupendously utilized in every zone of chemical industry. However, the dihydroxy substituted arylsulfone is rather more profoundly considered as structural entity of innumerable bioactive molecules of pharmaceutical relevance and is relatively difficult to synthesize. A novel waterassisted, catalyst-free carbon-sulfur bond formation strategy has been described for the direct access of highly valuable arylsulfonyl catechols. This protocol involves a direct Michael attack of aryl sulfinate produced from arylsulfonyl hydrazides as a nucleophile in aqueous media on in situ generated MOBs to form carbon-sulfur bond. Mechanistic studies suggested that water molecule play key role in the synthesis of catechols. Thus sulfonylation operates under mild conditions, shows broad substrate scope, gives high conversion and can be applied for gramscale synthesis (Scheme 2). The arylsulfones further synthetically transformed into molecules that are important precursors for drug discovery especially the analogues of COMT inhibitors the anti-Parkinson’s agents and the novel precursors for the treatment of obesity (Scheme 3). Scheme 2: Synthesis of arylsulfony catechol derivatives in aqueous media. vi Scheme 3: Synthetic transformation of arylsulfonyl catechols. 2.3. -Arylation and Synthesis of meta substituted phenols The enolate arylation of 1,3-dicarbonyl compounds and -cyanoacetates has drawn extensive and revolutionized attention as one of the significant methods for the C–C bond formation, which provides an easy access to complex organic frameworks. Owing to the utilization of -arylated 1,3-diones and ethyl cyanoacetates as prime substrates for synthetically useful transformations, we exploited the nucleophilicity of various C–H activated acids. Hence, we presented a base-mediated, direct highly convenient strategy for the C-arylation of C–H acti- Scheme 4: -Arylation of C–H activated pronucleophiles. vii vated pronucleophiles with various phenol derivatives as aryl partners. The present work excelled in forming C–C bond at the meta-position/site of the phenols which is traditionally challenging to achieve (Scheme 4). Underlining the utility of the obtained products, one-pot, straightforward, clean, high yielding routes for the synthesis of phenol substituted heterocycles such as pyrazoles, isoxazoles, coumarins, triazolones and carboxylic amide were demonstrated, which led the way for the endowment of important biological scaffolds (Schemes 5 and 6). Scheme 5: Synthesis of phenol substituted pyrazoles and oxazoles. Scheme 6: Transformation of cyano-substituted products. 2.4. Synthesis of substituted-5-aryl barbituric acid Since 1864, when German chemist Adolf von Baeyer discovered the barbituric acid, barbiturates are privileged with 1,3-diamide scaffolds in medicinal chemistry, because of their sedatives, anti-convulsants, analgesic, hypnotic, antimicrobial, anaesthetic, anticancer and antitumor properties. Although unsubstituted barbituric acid itself does not show any hypnotic or anticonvulsant properties; such features are conferred only when the active methylene viii hydrogen atoms at C-5 are substituted. Thus, we have delineated a general, straightforward approach involving the Michael addition of methylene carbon of barbituric acid derivatives to in situ generated ortho-benzoquinone monoketals for rapidly assembling the phenol functionalized 5-aryl barbiturates (Scheme 7). Scheme 7: Synthesis of 5-aryl barbiturates. Further, we have elaborated the utility of 5-aryl barbiturates through the construction of fully substituted barbituric acids consisting in-ring quaternary center. Spurred by the great synthetic medicinal interest of fully substituted barbiturates the 5-aryl barbiturates are subjected to sequential C–H alkylation using various alkyl halides for the synthesis of carbon as well as oxygen alkylated 5-aryl barbiturates (Scheme 8). Scheme 8: Synthesis of fully substituted barbiturates. Chapter 3: Experimental The third chapter provides experimental procedures in detail along with physical constants and spectral data including melting points, IR, 1H NMR, 13C NMR and HRMS data.